Preparation of delta9(11)-anhydro steroids



2,946,811 Patent d July 26 1 50 I 2,946,811 PREPARATION or A m-ANHYDRO STEROIDS "Earl M. Chamberlin, Westfield, and TorleifUtne, Warrenville, N.J., assignors to Merck & Co. Inc., Rahway,

NJ., a corporation of New Jersey I No Drawing. FiledMar..29',"19 57, Ser. No". 649,30 1

10 Claims. (11. zed-#39145 i This invention relates to the preparation of steroids,

and particularly, to the preparation of A -anhydro steroids from llfl-hydroxy steroids.

This application is a continuation-impart four application Serial No. 489,768, 'filed in the United States Pa'tent Office on February 21, 1955, now abandoned.

It has been suggested to prepare n 'i-anhydro steroids from llfi-hydroxy steroids by treating with phosphorous oxychloride in pyridine. It has also been suggested to carry out this reaction with a mixture of acetic acid and hydrochloric acid, as Well as, with acetic acid alone in the presence of a catalyst, such as, hydrogen bromide. The efiectiveness of those various methods depends to a large extent upon the particular llfi-hydroxy steroid employed. In using the phosphorous oxychlorid'e. method, an 'l'lfi-hydroxy-pregnane will be converted to thecorresponding A -anhydropregnene in relatively good yield, although :it usually requires an extended period of time,'at room temperature, to completeithe reaction.

When an llfi-hydroxy-n -pregnene:is' converted to the icorrespond'ing A -anhydro-pregnadiene, the yield,

however, is relatively small. A- relatively highiyield of product may be obtained after extensive "reaction time, fwhen the starting material is 'a compo'und' having keto acid with a hydrogen bromide catalyst results in only fair yields and requires an'extensive period of reaction time.

It has been suggested to subject lla-hydroxysteroids,

after first acylating any 21-hydroxy' group, to tosylation to form the corresponding lla-tosylate compound. The

latter compound is then reacted with sodium acetate and boiling acetic acid to form the corresponding A anhydro steroid. This reaction difiersfrom the reactions mentioned above, in that, it requires two'distinct steps to remove the llav-hydroxy group and form a double bond V v 2 uniformly good results. Other objects and the advantages of invention will appear hereinafter.

In accordance with'the invention llfi-hyd'ro-xy steroids areconverted to the corresponding A p-anhydro steroid bytreating with an alkyl halosulfinate. The alkyl halosulfinate is of the formula RO-SX' wherein R is an alkyl group preferably having a carbon chain length of from one to eight carbon atoms and Xis a halogen group preferably a chloro or bromo group. Typical examples of such compounds which maybe mentioned are methyl chlorosulfina'te, ethyl chlorosulfinate, propyl chlorosulfinate, butyl chlorosulfinate, methyl bromosulfinate', ethyl bromosulfinate, propyl bromosulfinate, a-chloroethyl-chlorosulfinate and oc-ChlOtOGthYl- .brornosulfinate. The lower alkyl (from one to four carbon atom chain) halosulfinates are distinctly advantageous because the reaction may be carried out at more desirable reaction conditions since they have lower decomposition temperatures. The alkylhalosulfinate is usually used in an amount ranging from one to ten moles per mole of ll/r-hydroxy steroid and preferably greater than two moles per mole of steroid.

In a preferred embodiment 'of the invention, the reaction is carried out with the, alkyl halosulfinate in the presenceof an acid-binding agent.- T ypicalexamples of classes of such agents are organic amines such as pyridines, N-alkylmorpholines, N-alkyl-piperidines,lutidines, collidines; trialkylamines, dialkylacylamides and inorganic bases; Of particular mention are the more readily available members of these groups, such as pyridine, N-methylmorpholine, N-ethylmorpholine, u,'yllltldille, collidines,

trimethylamine, triethylamine, tripropylamine dimethylaniline, diethylaniline, .N-arnylpiperidine, N-butylpiperii dine, N-ethylpiperidine, N-methylpiperidine, N-heptylpiperidine, dimethylformamide, diethylformamide, dimeth ylacetamide, N-propylpiperidine, sodium carbonate, sodium: bicarbonate and other alkali-metal carbonates and bicarbonates. The agent is preferably present in from one to ten moles for each 'mole of steroid. The agent at position 9(11). 'Thi's methodfhas not been applied to llflehYd-I'QXY steroids, because Whent he hydroxy group is in their 'configuration it is not'subject to tosylation, except under such severe conditionsastocause-the --de struction of the molecule; This is especially the case with a steroid having a.177position ltetal-side. chain because ,ofthe recognizedlability of such a side chain,. and also with steroids. having a doublejbond at the 4 position which It is an object of this invention to provide a simplified procedure for converting llp-hydroxy steroids to the r which can be.applied -to.a broad Ygroup-rof steroids with I selected .is preferably one that is also a solvent for the .1lB hydroxy steroid, such as pyridine, lutidin e, dirncthylformamide or dimethylacetamidel The reaction is conveniently carried out in a solvent for the. steroid. The solvent, as mentioned above, may

also serve as the acid-binding agent. The solvent may also be a mixture of ahydrocarbon andan acid-binding agent, such as benzene-pyridinemixture ora mixture of aclflorinated hydrocarbonand anacidbinding agent, "such'yas methylene chloride and pyridine. Other solvents which maybe mentioned are tetrahydrofnran, chloroform, acetone, propyleneglycol, methyl. ethyl ketone and anhydrous mixturesof these solvents.

Thetiine required for the reaction will depend, in part,

upon the particular reactants, solvents, and temperatures.v

At room temperature of ;,25'-30 C., the reaction usually requires approximately one-half to three hours when-a lower alkylhalosulfinate is used. Attemperaturesoffrom 15 C. to 0- C., the time maybe increased to four to ten hours}; The reaction is preferably carried out-aha temperature of O C. or below because in this range maximumyieldis obtained, 1

corresponding- A anhydro' steroids by this a process.

Z'Ihe :method iswell suitedto 1 dehydration of 1-1[5'.-hydroxy pregnanes and unsaturated pregnanesr flhepresence of other substituents in the moleoulesuch as keto groups at the 3 or 20 positions or hydroxy groups at the 3,170;

011*21 positionsforthepreseneejof double bonds, *as in Any of the llfl-hydroxy steroids having a hydrogen .atom attached to the 9-positionqmey be converted to-the 3 the 1:2, 4:5, 5:6 or 16:17 positions, does not interfere with the reaction. It is desirable, however, to esterify a hydroxy group, if present, at the 21-position.

The reaction is of particular value for dehydration of 11 fl-hydroxy pregnanes having a double bond attached to the C-5 position, since heretofore a method for converting such compounds to the corresponding A -anhydro compounds in high yield and in a relatively short reaction time was not available.

Such unsaturated pregnanes ordinarily are oxygenated at the 3 and 20 positions, and may also have hydroxy groups at the 17 and 21 positions as Well as at the 11,8- position. In addition to a double bond attached to the C-Sposition, i.e. a 4:5 or 5:6 double bond, they may also be unsaturated in the 1:2 position and elsewhere in the molecule.

Particular examples of llB-hydroxy steroids suitable for our process are the 21-esters of A -pregnene-11p,l7a,2ltriol-3,20-dione, such as the acetate, propionate, formate, butyrate, benzoate, t-butylacetate, hemisuccinate and phenyl acetate esters; and A -pregnene-116,17u-diol-3,20- dione; A -pregnene-11B-ol3,20-dione; A -pregnene-1 15,21- diol-3,20-dione 21-acetate; acetate esters of A -pregnene- 1lfi,17a,20,21-tetrol-3-one; M-androstene-l1B-ol-3,17-dione; pregnane-l 1p-ol-3,20-dione; pregnane-1l/3,21-diol-3, 20-dione 21-acetate; pregnane-l1B,17a,2l-triol-3,20-dione 2 l-propionate; allopregnane-l 1B, 170c,21-tliOl-3,20-di0116 21 butyl acetate; A -pregnene-3fl,l1B-diol-20-one; A pregnene 11/3,17cc,21 triol 3,20 dione- 21 acetate 3,20-bis-ethylene ketal; A -pregnadiene-11/8,l7a,21-triol 3,20-dione 2l-lower acylate (such as the 2l-acetate, propionate, butyrate and t-butyl acetate); A -pregnadiene- 1lB,21-diol-3,20-dione 21-acetate; A -pregnadiene-l1B, 17w'diOl-3 ,20-dione; A -pregnadiene-I1fi,21-diol-3,20-dione 21-acetate and N-allopregnene-l1fl,17a,21-triol-3,20- dione ZI-acetate.

The A anhydro-pregnanes and unsaturated pregnan'es and the A -anhydro-allopregnanes and unsaturated allo-pregnanes obtained by our process are useful as intermediates in the synthesis by known methods of physiologically-active 9oc-halo-11e-hydroxy steroids of the .hours.

pregnane series unsaturated in at least the 4:5 position.

The following examples are given for purposes of illustration:

7 Example 1 p A 4.05 gram sample of M-pregnene-l1fl,17oe,21-triol-3, 20-dione 21-acetate is dissolved by heating in 150 ml. of dry tetrahydrofuran and the resulting mixture cooled to 1' 0 C. 'Dry pyridine (8 ml.) is then added to the cooled mixture followed by 11.5 grams of methyl chlorosulfinate at such a rate to maintain the temperature at 10 C. to 5 C. The reaction mixture is then allowed to warm to room temperature (20-30 C.) over a period of four hours. The A -pregnadien-17a,21-diol-3,20- dione ZI-acetate is precipitated from the reaction mixture by the addition of 150 m l. of ice water. The productis filtered after aging for one-half hour and washed with cold water. Yield 3.45 grams, melting point 226-230 C.

' Example) A 4.0 gram sample of A -pregnene-11fl,17u,21-triol 3, 20-dione 21-acetate is dissolved in 20 ml. of dimethylformamide. added to the mixture while maintaining the temperature between 20 2550. by external cooling, The reaction mixture sets to a semisolid mass shortly after theaddition of the sulfinate is begun. Thirty minutes afterthe addition of the methyl chlorosulfinate, 70 cc. of methanol are 11.5 grams of methyl chlorosulfinate is filtered and washed with methanol and then recrystallized 4 21-acetate are dissolved with heating in 1.65-1.70 m]. of pyridine and 31 ml. of tetra-hydrofuran. The solvents are dried over potassium hydroxide prior to use. The mixture, protected from the atmosphere with a drierite tube,

is chilled to 10 C. and treated, with constant stirring, with 1.80 ml. of methyl chlorosulfinate. The temperature is maintained at about -10 C. during the addition. A crystalline solid which separates at the beginning of the reaction subsequently turns into an oil. The reaction mixture, after standing at room temperature for four'hours, is chilled and treated with about 200 ml. of a 5% solution of sodium bicarbonate. The treatment with base converts the oil again into a crystalline solid.

The solid, after aging at room temperature overnight, is removed by filtration and washed copiously with water. The filtrate is extracted with ethyl acetate and the extracts are combined with a solution of the wet crystalline solid inthe same solvent. .The ethyl acetate solution is washed twice with a saturated salt solution and then evaporated to dryness. The crude product is recrystallized from methanol-water to give purified A -pregnat1ien-17a, 21-diol-3,20-dione ZI-acetate. One additional recrystallization by displacement of acetone with petroleum ether afiords substantially pure material, melting point 216- 220.5 C.,

Example 4 A solution of 2.0 grams of pregnane-11fl,17a,2l-triol- 3,20-dione 21-acetate in 3 ml. of dry pyridine and 70 ml. of dry tetrahydrofuran is cooled to about -10 C.

4.0 ml. of methyl chlorosulfinate are added to the cold stirred solution of steroid. The mixture is allowed to warm to room temperature over a period of about five It is then cooled and treated with 400 ml. of 5% 1 aqueous sodium bicarbonate.

V The solid material which forms upon the bicarbonate treatment is filtered, washed well with cold water and dissolved methyl acetate. This organic solution is washed successively with sodium chlowhere R is lower alkyl and X is selected from the group consisting of chlorine and bromine.

2. The process of claim 1 wherein the reaction is carried out in the presence of an acid binding agent.

3. The process-for preparing a A -3,20-bisoxygenated-17a hydroxy-21-1ower alkanoyloxy steroid of the pregnane series that comprises reacting a steroid selected from the group consisting of 1lfl,l7a-dihydroxy-3,20-bisoxygenated-21-lower alkanoyloxy-A -pregnenes and 1113,- 17a-dihydroxy-3,ZO-bisOXygenated-Z1=lower alkanoyloxy- A -pregnenes having a hydrogen atom attached to the C 9 position with an alkyl halosulfinate of the formula where is lower alkyl and X is selected from the group 'consistmg of chlorine and bromine.

4. The process of claim-3 wherein the action is carried out in the presence of an acid binding agent.

5. The process for producing A -pregnadien-17a, 21-dio1*3,20-dione-21-lower-alkanoate which comprises reacting A -pregnene-11p,17u,2l-triol-3,2O-dione-2l-loweralkanoate with a lower alkyl chlorosulfinate.

6. The process of claim 5 where the 2l-1ower alkanoate is the acetate and the lower alkyl chlorosulfinate is methyl chlorosulfinate.

7. The process of claim 6 wherein the reaction is carried out in the presence of an acid binding agent.

8. The process for producing A -pregnatrien-17a- 21-diol-3,20-dione-21-lower-alkanoate which comprises re- References Cited in the file of this patent UNITED STATES PATENTS 7 2,763,771 Fried et a1 Sept. 18, 1956 

1. THE PROCESS FOR PREPARING A $9(11)-3,20-BISOXYGENATED STEROID OF THE PREGNANE SERIES THAT COMPRISES REACTING A STERIOD SELECTED FROM THE GROUP CONSISTING OF 11BHYDROXY - 3,20-BISOXYGENATED-$4-PREGNENES AND 11B-HYDROXY-3,20-BISOXYGENATED-$5-PREGNENES HAVING A HYDROGEN ATOM ATTACHED TO THE C-9 POSITION WITH AN ALKYL HALOSULFINATE OF THE FORMULA 